Expandable Dehydrated Human Umbilical Cord Allograft for the Management of Nonhealing Lower Extremity Wounds in Patients With Diabetes: A Case Series

The first reported use of amniotic membrane in medical procedures dates to 16^th century China,¹ and its initial use as a wound dressing or skin substitute appears in the Western medical literature in the early 1900s.² Attempts to use the rich extracellular materials of the placental plate have been explored; however, to reduce the risk of an adverse immunologic reaction the tissues must first be decellularized, as with other allografts and xenografts. The DHACM allograft is an immune-privileged, minimally manipulated, dehydrated, nonviable cellular human amniotic membrane allograft that contains over 250 identified preserved regulatory factors.^3,4

In contrast, only in the past decade have researchers begun to investigate the use of the structural and biochemically active components present within the umbilical cord.^5–8 The umbilical cord is a tissue that some have identified as a separate organ in its own right.⁹ Relatively acellular and rich in regulatory compounds and extracellular matrix, this material is a thicker, structured allograft for wound closure. The DHUC allograft is a minimally manipulated, dehydrated, nonviable cellular umbilical cord allograft.⁵ Its advantages over amniotic membranes include a thicker, sturdier scaffolding and an ability via meshing to be expanded over a wound while providing a protective environment that supports the healing cascade.⁶

The clinical safety and efficacy of DHUC as a treatment for nonhealing DFUs was previously established in a multicenter prospective randomized controlled trial.⁶ In that study, when patients received adequate debridement, 96% of DHUC-treated DFUs closed completely within 12  weeks, compared with 65% of alginate-treated ulcers (P <.0001).⁶ Preclinical testing in a rat subcutaneous implantation model demonstrated an increase in stem cell proliferation (adipose-derived and mesenchymal), fibroblast migration, and endothelial progenitor cell vessel formation in a dose-dependent manner after DHUC stimulation.⁵ In addition, umbilical allografts were resorbed without fibrous encapsulation.⁵

In utero native placental tissues contain an array of growth factors that play essential roles in regulating tissue development and growth. Epidermal growth factor, transforming growth factor alpha and beta, vascular endothelial growth factor, and tissue inhibitors of metalloproteinases are a few of the regulatory proteins that play a critical role in the physiologic processes required for healthy tissue repair and that are found in DHUC.^3,5,10,11 The DHUC contains factors that are known components of a scaffold, such as collagen I, hyaluronic acid, laminin, and fibronectin, in addition to 461 proteins (growth factors, cytokines, inflammatory modulators, chemokines, proteases and inhibitors, adhesion molecules, signaling receptors, and other soluble regulators).⁵

Herein, the authors report scenarios (stalled previous treatment, poorly perfused tissue, alternative to invasive treatment) in which DHUC was beneficial in achieving wound closure; invasive skin graft techniques were avoided because DHUC can be stitched, though stitching was not necessary for the cases presented.⁶ The 2 cases detailed involve a chronic heel ulcer and closure of a wound following excision of a hidradenoma from the plantar aspect of the foot. In both cases, favorable outcomes were achieved using umbilical allografts in combination with other treatment modalities.

Both patients in the cases reported herein provided the primary author (MG) with written informed consent to use images obtained during treatment and to publish case details. Institutional review board approval was not required.

Wound cleansing was performed at the clinic, and measurements were taken. Sharp debridement was performed to expose viable bleeding tissue in the ulcer bed and to ensure no significant, callous, devitalized tissue, epibole, or foreign material present in or around the wound. Negative pressure wound therapy was used as necessary. Patients were instructed to keep dressings clean, dry, and undisturbed. Offloading, foam dressings, and compression therapy were used as appropriate based on wound stage at clinical presentation.

Both patients were refractory to standard care and were elevated to advanced wound therapies after approximately 1 month. Initially, DHACM (EPIFIX; MIMEDX Group Inc.) was cut and applied to fit the wound as appropriate. Wounds were considered stalled for the 2 patients in the current report if 50% closure was not achieved after 1 month to 5 months, at which time DHUC (EPICORD; MIMEDX Group Inc.) was used. The DHUC was rehydrated for approximately 10 seconds in a saline bath. The limited size of umbilical tissues has resulted in approaches to maintain its effectiveness over a larger area, including meshing, a strategy often used in skin grafting. The DHUC EX was cut to fit the desired area after rehydration of the product. A nonadherent contact layer was placed over the allograft, followed by appropriate moisture management dressings.

Case 1

The first case is of a 62-year-old male with type 2 diabetes complicated by peripheral neuropathy in addition to a 6-month history of a refractory stage 3 right heel pressure injury that developed secondary to immobility (bedridden) (Figure 1). Past medical history was remarkable for prior calcaneal osteomyelitis, amputation of the right fifth toe secondary to gangrene, renal cancer, chronic anemia requiring regular transfusions, hypertension, hyperlipidemia, asthma, depressive mood disorder, and other conditions.

Before presentation, the patient’s right heel ulcer remained refractory to closure despite conservative outpatient therapy that included foam dressings and offloading. The initial examination revealed scattered areas of fibrotic tissue mixed with areas of pink granulation tissue (Figure 2A). After debridement to viable bleeding tissue was performed, a decellularized human collagen matrix tissue along with another amnion-based granular product and foam dressing were placed over the ulcer bed to help prepare the wound bed (Figure 2B). This was repeated every 2 weeks for approximately 5 months. Five months after initial presentation the wound still measured 5.5 cm × 1.7 cm × 0.1 cm, at which time more aggressive options were considered, including skin grafting. The decision was made to switch to DHUC EX. The material was rehydrated and expanded over the right heel ulcer to obtain wound coverage (Figure 2C). Suturing the allograft was considered, but it was deemed unnecessary.

After the initial application of DHUC EX, the patient did not return for follow-up for approximately 2 months. Despite the patient’s extended absence, by that time the ulcer had decreased in size by 84% (Figure 2D). A second DHUC EX, measuring 1.5 cm × 1.0 cm × 0.1 cm, was applied to cover the wound (Figure 2E). The patient returned to the clinic 7 days later, by which time the ulcer had further decreased in size by 44% (measuring 1.2 cm × 0.7 cm × 0.1 cm) (Figure 2F). The decision was then made to transition treatment of the right heel ulcer to a smaller DHACM allograft disc for coverage. One week after DHACM application, complete epithelialization of the right heel pressure injury was observed (Figure 2G).

Wound closure was achieved with a combination of several products, but use of DHUC most notably accelerated closure. No adverse events or complications were noted with the use of either DHUC or DHACM allografts. The results were durable, and improvements in the region of the resolved right heel ulcer were noted on subsequent clinic visits. The appearance of the DHUC EX before and after rehydration is shown in Figure 3.

Case 2

A 72-year-old male with type 2 diabetes presented after excision of a hidradenoma from the plantar aspect of the left foot. The patient had an HbA_1c level of 7.1, with palpable pulses and intact sensation. The patient’s course was complicated by dehiscence of the left plantar surgical wound (Figure 4, Figure 5). Before the patient presented to the clinic, the wound had been treated for 6 weeks with cadexomer iodine and DHACM, which resulted in filling of the wound bed with granulation tissue but little change in wound dimensions. (Images before the patient’s presentation to the wound clinic are not available.) The wound was also treated with topical lidocaine gel for pain relief and sharp debridement to remove biofilm. After 6 weeks of standard care (ie, after debridement), the patient had an initial wound care visit and the wound measured 6.5 cm × 3.5 cm × 0.2 cm (Figure 5A). The wound treatment was then changed to DHUC EX bolstered with a disposable mechanical NPWT device (Figure 5B, 5C).

After 1 week, the wound had decreased in size by 43% from baseline (measuring 4.8 cm × 2.7 cm × 0.1 cm) (Figure 5D). A second treatment with a combination of DHUC EX and NPWT was applied (Figure 5E). The umbilical graft remained well positioned, and no sutures were used. When the patient returned to the clinic after 2 weeks, the wound had decreased in volume by 53% from baseline (Figure 5F). The wound continued to respond to the umbilical allograft treatments, and a third DHUC EX was applied when the wound measured 4.0 cm × 2.7 cm × 0.1 cm (Figure 5G); DHUC EX was applied for 2 additional weeks. Figure 5H demonstrates ongoing wound closure at +4 weeks, after 3 applications of the DHUC EX barrier. Complete epithelialization of the wound was observed at week +6 of the weekly clinic visits (Figure 5I). No adverse events or complications were noted with the use of the allografts. The results were durable in case 2 as well, with wound site improvements noted on subsequent clinic visits.

The refractory nature of chronic DFUs is multifaceted. Factors that contribute to delayed closure include disrupted signaling cascades that mediate cell recruitment and crosstalk between cells, persistently elevated metalloproteinase levels, profound disturbances in the bacteria-host relationship, neuropathy, peripheral arterial disease, and impaired immune function. Given the high frequency and high costs associated with treating DFUs, techniques that promote more rapid and complete closure are warranted.^12,13

This case series discussed 2 patients with diabetes, 1 of whom presented with a heel ulcer and the other with a chronic wound of the plantar aspect of the foot; both wounds showed little response to 1 to 5 months of previous therapy. Coverage of the wounds was facilitated by the expandability of DHUC EX. The thicker allograft was appropriate for the depth of the wounds. Suturing was considered in both cases but was deemed unnecessary; however, it is occasionally necessary in some complex wounds. Additional benefits of DHUC may be conveyed by the complexity of the 461 proteins identified within it,⁵ compared with DHACM (> 250 proteins).^3-5 In both cases, wound sizes began to decrease immediately upon use of umbilical allograft, and durable wound closure was achieved.

A recent retrospective analysis of Medicare patients with DFUs noted that changing to advanced treatments (including placental-derived allografts) within 30 to 45 days of diagnosis and application of such treatment at 1-week to 2-week intervals reduces amputations and health care utilization.¹³ In that study, a savings of $3670 per patient was realized in the first year with use of DHACM. In the current report, the previously stalled wounds responded rapidly to DHUC; this reinforces previous findings that improved outcomes, reductions in health care utilization, and cost savings can be achieved with appropriate migration of stalled wounds to advanced therapies, including umbilical cord allografts. Additionally, umbilical allografts are applied in an outpatient setting, which avoids the associated expense of operating room costs required for skin grafts. In patients with plantar ulcers, achieving epithelialization during closure by secondary intention is preferred to split-thickness skin grafting owing to the superior durability of closure with the former method.

In cases in which wound closure is elusive, changing to an advanced wound therapy is warranted.¹⁴ Umbilical cord-derived allografts offer benefits in the management of deeper, poorly perfused, recalcitrant wounds, as observed in the cases reported herein. Starting advanced treatments (eg, skin substitutes) earlier rather than later and applying them in a consistent manner thereafter can favorably affect patient outcomes.¹³ The thickness and meshed properties of DHUC EX allow for coverage of larger wounds and suturing for more secure allograft placement. Patients can be treated in an outpatient setting, thus avoiding the associated expense of operating room costs and offering a practical alternative to the use of full-thickness skin grafting on plantar surfaces.

Limitations of this case series include the retrospective design and small sample size. Additionally, both patients received multiple treatments, which can confound the evaluation.

From this report, the use of DHUC EX demonstrates a viable approach to closing refractory wounds. This treatment was selected for the current cases after previous attempts with other advanced wound care approaches failed to close the wound, per institution protocol (ie, to suggest changing treatments for stalled wounds).

A prospective randomized controlled trial to evaluate umbilical cord-derived allografts vs amniotic allografts in larger, deeper wounds should be considered in addition to a cost-effectiveness analysis comparing umbilical cord-derived allografts with standard wound treatments. The availability of placental-derived allografts in different configurations allows the clinician to select the most appropriate advanced treatment for various wound characteristics to create an optimal barrier over the wound bed and an environment that supports the rebalancing of the healing cascade. This may potentially expedite time to closure, reduce the use of medical resources (eg, emergency department visits, readmissions), and lower overall costs.